From Jones and Bartlett, a book on Stem Cells from Dr. Ann A. Kiessling and Scott C. Anderson:

Selected Articles:

May 20, 2004

Who Needs Sex?

Is there another way to mix genes besides sex?

By Scott Anderson

An intriguing idea percolating through the scientific community has the power to upend a lot of biology, genetics and evolution. For that reason, scientists are treating it delicately. They are poking at the theory (because they must), but from a respectable distance. The idea, called "horizontal gene transfer," makes a terrific sci-fi premise - but it may also be true.

We're used to the idea that our genes come from our parents, who mixed and matched their own genes to create each of us as a unique individual. That's certainly what Mendel showed with his pea studies, and what countless follow-up experiments have amply confirmed. You can illustrate these experiments with genetic trees showing children branching off from their parents and having more children, etc.

Scale the tree up to include all the species, and you have a tree of life.

There are two things to notice about a standard tree of life. One is that it has a single starting point at the base of the trunk, which presumably represents the original cellular life-form from which all subsequent life evolved. Around 3.5 billion years ago, this original prototype cell must have bubbled up out of the primordial sludge and mutated into different cells that eventually established the basic domains (also called kingdoms) like bacteria, plants and animals.

The second thing to notice about the standard tree is that the branches inexorably go up and out. After a species splits off, it never looks back. In fact, that's what we mean by species: creatures of the same species can successfully mate and produce offspring, but after the split has been made inter-species mating is sterile. The branches spread out and the genes never again get a chance to mix.

Classic Darwinian genetics is a paragon of patience. Tiny changes slowly accumulate over many eons, finally converting, say, a brown-eyed gene into a blue-eyed gene. The changes are presumed to be random, but over a sufficient period of time, certain genes demonstrate a statistically reliable rate of change. That rate can be used to calibrate a kind of clock: if a gene averages one change per millennium and your two samples have ten differences, then they probably differ in age by ten millennia.

Having sequenced so many genes, and armed with this genetic clock, we should be able to a bang-up job on the tree of life. We should be able to pinpoint with reasonable precision when each species split off and even to quantify how different it is from its ancestors and cousins. But in working on the tree, a perplexing anomaly has surfaced.

Enter the Paradox

The problem is simple to state: the genes of many species seem to be younger than the species themselves. That's a big problem; if we want to use genes to refine the tree of life, it would be handy if they actually correlated with the species. Worse yet, certain genes seem to be popping up in more than one species - perhaps even more than one domain - at about the same time.

It's almost as if entire genes had been packaged up and transferred to other species. But that couldn't be - there are just too many cellular processes designed to stop this very thing. If genes were that promiscuous, it would throw biology for a loop. Besides, how could something as dramatic as wholesale gene transfer be overlooked by the last seventy years of molecular biology? 

Recognizing gene transfer, however, is not so simple. Before all the genes had actually been mapped and logged for analysis, seeing the patterns was a matter of serendipity. However, once the data started flowing in, an interesting picture started to emerge - and it wasn't what anyone had expected.

The first hints that whole-gene transfer was possible came from studies of antibacterial resistance. Antibacterial action was discovered in 1928 by Alexander Fleming, who noticed that a spot on mold in a petri dish was killing his colony of staph bacteria. Fleming isolated penicillin from the mold and created the first mold-based antibacterial.

Many more antibacterial extracts were discovered, and these had a huge impact on the health of humans around the world. But within years of using some of these antibacterials clinically, the bacteria started to develop resistance. At first a mystery, the cause of the resistance was finally traced to genes on a circular loop of DNA called a plasmid. These loops of DNA are passed back and forth by the bacteria as casually as you would loan a DVD to a friend. And, as with a DVD, the DNA is standardized and ready to "play" in any other bacteria. If the plasmid confers resistance to a particular antibiotic, any cell that receives it is then protected. The bacteria without the gene die off, leaving a population of "super bugs" that can't be treated with that particular antibiotic.

Okay, thought the researchers, that is certainly gene transfer, but a bacterial plasmid is nothing like the nuclear DNA in more advanced organisms. What's true for bacteria surely has nothing to do with eukaryotes (the so-called "true" cells of plants and animals). Eukaryotes, it was certain, only mixed genes during the cross-over event of sexual reproduction. In fact, thanks to the pioneering work of people like Barbara McClintock, scientists had actually succeeding in nailing down just where each gene resided on the chromosomes. If there was ever an orderly, static place for storing information, it was the stately DNA molecule.

But then in 1951, McClintock, who clearly didn't know how to rest on her laurels, noticed something in a special variety of corn that is still creating ripples throughout biology today: some of the genes were jumping around to different locations on the chromosomes. Not only that, but there were other genes helping them do it. McClintock called it transposition, and the jumping genes became known as transposons.

This news didn't go down easily. Many scientists insisted that the effect must be limited to that specific corn variety - a freak of nature, certainly not the norm. But Dr. McClintock disproved that notion when she discovered more transposons in other varieties as well. That should have settled the case, but many scientists remained unconvinced and minimized the importance of jumping genes. Even though she received a Nobel prize for her work, Dr. McClintock's experiments are still little known outside of biology labs.

In the 1960s, Lynn Margulis declared that organelles (tiny structures in cells like mitochondria or chloroplasts) are most likely trapped bacteria that have come to live symbiotically within eukaryotic cells. Once again, biologists were intrigued but wary. Bacteria are supposed to be our enemies, and yet here was Dr. Margulis suggesting that we had let the enemy in the front door and were setting up house with them. So now, it seemed, not only genes were being transferred, but whole organisms were being co-opted. The Darwinian struggle was starting to look more like a love fest.

In 1976, Susumu Tonegawa at MIT discovered that mouse antibody genes change their positions on the chromosomes, in effect randomizing the antibodies. By shuffling the genes like this, millions of different combinations are generated, allowing antibodies to attack a wide range of invaders. This is a case where jumping genes are used to promote parsimony; to actually encode each antibody as a unique gene would easily quadruple the size of the chromosomes.

Loose Genes

In the 1980s, Harvard's Dr. Michael Syvanen couldn't stop thinking about the many different ways that a gene might be passed around from species to species. For instance, as well as using plasmids to transfer genes, bacteria were known to pick up genes merely by eating a fellow bacteria - even one from a different species. You are literally what you eat, at least when it comes to bacteria.

And if bacteria can easily incorporate genes from their surroundings, they may pick up animal genes as well. In fact, certain strains of luminescent bacteria are known to have an animal variety of a gene called superoxide dismutase. Presumably, the gene was picked up from the ponyfish that, over the ages, have provided a symbiotic home for the bacteria.

That conjures up some unsettling scenarios. Bacteria are, after all, responsible for decay, the system by which all flesh is ultimately converted to compost. Just by consuming animals, bacteria may pick up genes from those animals. And if, say, a vulture dines on that rotting flesh, those bacteria may take up residence in the bird and possibly even pass a gene from the dinner to the diner. Like I say, a good premise for a sci-fi story.

As well as bacterial vectors, Dr. Syvanen knew that retroviruses can also inject whole genes by hijacking the cellular reproductive machinery and splicing the gene into the cell's own DNA. There is also some evidence that viruses, like bacteria, can pick up genes from a host. Might they then pass these on to another host?

When the human genome was sequenced, the tally was incredible: humans were found to have at least 98,000 of these spliced-in viral genes liberally peppering our chromosomes. How did they get there? Apparently, a virus infected a precursor to a germ cell (such as a sperm), which incorporated it into its nuclear DNA and then passed it on after fertilization to its progeny. And, apparently, that has happened about a hundred thousand times throughout our genetic history.

Some of these genes are implicated in cancer and auto-immune diseases, although most of them seem to be inactivated. Nevertheless, if any more proof of gene transfer was needed, this would seem to cinch the case.

But dogma can be surprisingly tenacious, especially when the very essence of humanity is concerned. Are we just a hodge-podge of foreign genes and body parts tossed together from various sources? As ideas go, they don't come any more preposterous than that. It's insulting to the human species to suggest that we are pasted together like some crude ransom note, using arbitrary bits and pieces snipped out of other creatures.

And yet, as Dr. Syvanen (now at UC Davis) and others have pointed out, this preposterous theory explains so much. For instance, why is the DNA code the same for all creatures, no matter how many billions of years ago they separated? Why are the same 20 amino acids encoded pretty much the same way for all creatures? It doesn't seem to square with simple thermodynamics (things break down over time), let alone popular notions of biological diversity. But if genes are being passed around like shared DVDs, they would all need to run on the same operating system to be useful. Any creature that couldn't share the genetic information would be marginalized and could even become extinct, and that would exert a Darwinian pressure for conformity to a single code. It is a rather elegant theory.

Along with the captured organelles of Dr. Margulis, it implies a less cut-throat environment for evolution. Instead of an all-out brawl, there are firm guidelines that most organisms follow, and opportunism abounds. A gene - or even an entire creature - is as likely to be exploited as exterminated. Instead of a fight to the finish, networking is the order of the day.

Gene transfer also helps to explain the sudden changes noted in the fossil record. Typically, rather than the stately progression of "ordinary" Darwinian evolution, relatively fast changes occur between long stretches of stability. Niles Eldredge and Stephen Jay Gould called it punctuated equilibrium, and argued that it represented new species splitting off and changing over tens of thousands of years. That is slow enough that no single individual would even perceive it, but by geological scales, it's an eye-blink.

The popular explanation for how a species splits involves physical separation between two populations, say by a flood-swollen river. Over time, if not exposed to each other, they could diverge genetically. But what if wholesale gene transfer were able to split a species in two without further ado? Could gene transfer be another agent of speciation, a kind of instant genetic barrier that ends up separating two populations molecularly?

Dr. Syvanen goes even farther. As every budding biologist learns, early human development looks a lot like monkey, chicken or even shark development. Human embryos have tails and gills that later disappear or morph into something else. Why the commonality of development? If Dr. Syvanen is right, the persistence of these similar forms provides a valuable platform for gene transfer. It might allow a shark gene to be expressed in a human being - at least during some phase of development. If so, there would be a strong evolutionary pressure to ensure that this platform for gene transfer was maintained. Without it, a major possible mechanism of cross-species genetic updating would be lost.

Not Just Academic

If gene transfer is common, it has far-reaching implications. Just as one instance, current genetically modified (GM) food crop experiments are being challenged because they threaten to spread their genes to other nearby crops. Dr. Syvanen's work would seem to support these concerns.

Currently, in order to create a GM plant, scientists use plasmids that contain the gene of interest connected to a gene for antibacterial resistance. After getting the plant to take up the plasmid, the researchers need to separate the plants that actually express the gene from those that didn't incorporate it properly. They do that by dosing the cells with antibiotics. If the gene of interest has been properly inserted, odds are the antibacterial gene will be too, and those cells will survive while the rest die off.

That means that most GM crops, simply as an artifact of their laboratory creation, have antibacterial genes. Can these transfer to bacteria in the soil? After what we've learned so far, it would be surprising if they didn't. In fact, that's just what people are finding when they look at the bacteria around the roots of GM crops.

But if gene transfer is really that profligate, then perhaps GM foods are not so special after all. It might seem totally wacky to put jellyfish genes into tomatoes, but it wouldn't be surprising if nature had already beat us to the punch. In fact, given the evolutionary gauntlet that genes must endure, it would be quite surprising if mere humans were able to put forward a novel gene that could possibly compete with the reigning champs.

In other words, nature is resilient, and genetic engineering may not be the sole province of human researchers. Mother Nature likes to mix and match too, and she has a few billion years on us. That's not to say we should feel free to muck things up. Certainly we can damage ecosystems by popping in the wrong gene. Due to the ruggedness of nature, we probably won't cause any runaway genetic meltdown, but we could easily make a mess if we don't take gene transfer seriously.

The lesson for GM researchers may be that the reason it is possible to insert genes in the first place is that life is built for swapping - but it doesn't stop at the lab door. The genes we introduce may spread throughout an ecosystem, so we should be circumspect about which genes those are.

If our genes are really jumping around, we need to rethink many things. The molecular clock we've been depending on to date all things biological may need to be recalibrated. Evolution, commonly thought of as the accumulation of billions of tiny changes, would be radically speeded up if whole genes are exchanged. And the whole tree of life starts to look more like a web, where the horizontal lines represent genes that have jumped from one species to another:

This is truly a remarkable picture that may overthrow some of our most cherished notions. If viruses and bacteria are indeed vectors for transferring genes, then their collective status as mischief maker should be revised to include species maker. Perhaps viruses and bacteria have more central roles in evolution than previously appreciated.

Jumping genes may also play a part in development, as stem cells morph into adult cells. There is accumulating evidence that contrary to what most of us learned in school, each cell does not have the same DNA. Instead, through a series of adjustments and jumping around, the genome is rearranged to provide a unique blueprint for each cell type.

Recent research has indicated that developing embryos produce reverse transcriptase. This is the protein used by retroviruses to sneak their genes into the host DNA. Why is a virus protein expressed during animal development? Based on what we've learned so far, we couldn't be blamed for thinking it's to help shuffle the genetic deck. In the process of shuffling, the subsequent daughter cells would differ from their mother - they would differentiate, which is the beginning of development.

Scientists already have theories to explain how a daughter cell can be different without invoking jumping genes. It's pretty easy to roll up a segment of DNA so that it is effectively neutered, and that should also give rise to differentiated cells. But what if both mechanisms (new genes and neutered genes) are needed?

Did a virus infect an early cell and inadvertently confer upon it the ability to specialize, thus giving rise to the first complex creatures?

Could these mechanisms have grown up together, one changing genes on the short scale of development and the other on the long scale of evolution? And, if the same mechanism underlies both phenomena, could gene transfer offer yet another way to explain why development echoes evolution?

Many more experiments and observations are needed to measure the full impact of gene transfer, but some biologists are still dragging their feet. A recent article in the prestigious journal Nature speculated on the origin of life as a sort of communal soup. There was not a single mention of horizontal gene transfer. I asked Dr. Syvanen about the slight, and he said that he has submitted several papers to Nature, but they have never been accepted. When I asked him if he was running into resistance from people whose timelines would have to be recalibrated, he said, "Major resistance. You are right. It would change the field of taxonomy, maybe not too seriously with the metazoans but with plants and the higher taxonomic issues it would."

Nevertheless, as with the theories of  McClintock and Margulis, the final arbiter of biological truth is not a committee of smart people, but rather nature herself. As much as it pains us, many of the things we learned in school were just plain wrong. That is, paradoxically, a mark of success for the scientific method.

When it comes to mixing genes, sex is a great, time-honored technique. But it may not be the only way. The next time you get the flu or an infection, stay alert to the possibility that your genes may be getting an update. For the sake of you and your future children, let's hope it's a good one.

Copyright © 2000-2014 by Scott Anderson
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Here are some other suggested readings in gene transfer: